The longterm objective of this research plan is to improve our understanding of the genetic specificity of immune recognition and of responses to major and minor histocompatibility antigens and to MHC-restricted antigens. We will use four approaches to determine the extent of serologically detectable genetic polymorphism within the human major histocompatibility complex (MHC): a.) to compare serologic reaction patterns of different ethnic and hybrid populations to identify antigenic variants, b.) to extensively characterize allo, xeno and monoclonal antibodies in order to identify definitive reagents for polymorphic allodeterminants, c.) to investigate whether serologically defined HLA-A and B allodeterminants are also recognized by cytotoxic lymphocytes and d.) to identify serologic and cellular reagents that distinguish different MHC class II subsets. A variety of serologic and cellular approaches will be taken to determine within the human genome, the identify and location of non-MHC linked histocompatibility antigens which induce acute allograft rejection and severe graft versus host disease in recipients of genotypically MHC identical allografts. Family studies will be carried out to confirm the mode of inheritance of new minor and major allodeterminants, and in recombinant families, to map genes within the MHC complex. Evidence for gene complementation leading to specific unresponsiveness in mixed lymphocyte reactions will be sought. We will investigate the genetic bases for significant associations between the MHC complex and certain diseases; namely idiopathic hemochromatosis and malaria. We will extend existing methodology for genetic analyses of human disorders, particularly those with delayed onset and multiple modes of expression, qualities characteristic of many immunologic disorders.